Tranquilizers

ABSTRACT

Tranquilizing agents for warm-blooded animals corresponding to the formula   Where n can be 1 or 2; Y can be --(CH.sub.2).sub.n -- or   Where R.sup.2 can be hydrogen or an alkyl, alkenyl, alkoxy, phenyl or methoxyphenyl radical. Z can be thenyl, furyl, phenyl; or mono-, di-, or trimethoxyphenyl, mono-, or dichlorophenyl, or dichlorophenoxy. R and R.sup.1 can be hydrogen, methyl, or ethyl and can be the same or different.

United/States Patent [\91 Wehrnieister" [451 Apr. 8, 1975 1 1TRANQUILIZERS [75] Inventor: Herbert L. Wehrmfeister, Terre Haute, 1nd.I

[73] Assignee: Commercial Solvents Corporation,

Terre Haute. 1nd.

221 Filed: Apr. 1, 1974 211 Appl. No.2 456,928

Related U.S. Application Data [62] Division of Ser. No. 312,242. Dec. 4.1972.

Primary E.\-aminer-Stan1ey .1. Friedman Attorney, Agent. or FirmRobertH. Dewey; Howard E. Post 57 1 ABSTRACT Tranquilizing agents forwarm-blooded animals corresponding to the formula ocH where n can be 1or 2; Y can be (CH or where R can be hydrogen or an alkyl, alkenyl,alkoxy. phenyl or methoxyphenyl radical. Z can be thcnyl. furyl, phenyl;or mono-, di-, or trimethoxyphenyl. monoor-dichlorophenyl. ordichlorophenoxy. R and R can be hydrogen, methyl, or ethyl and can bethe same or different.

14 Claims. No Drawings TRANQUILIZERS This is a division, of applicationSer. No. 312,242, filed Dec. 4, 1972.

BACKGROUND or THE INVENTION This invention relates to tranquilizingagents for warm-blooded animals. In a particular aspect, this inventionrelates to certain oxazines and oxazolines useful as tranquilizingagents.

Tranquilizing agents are very useful in calming animals. For example,they are very helpful treating sick animals and in the capture andtransportation of wild animals. Many tranquilizing agents are known,among which are oxazolines of the formula where R is halogcnyl phenyl,o-hydroxyphenyl or mtrifluoromethyl as disclosed by L. F. Wiggins etal., U.S. Pat. No. 3,235,557.

SUMMARY OF THE INVENTION are central nervous system depressants whichare useful in the calming of animals. In the formula, 11 can be 1 or 2;Y can be the group (CH where n is l or 2, or

where R can be hydrogen, or an alkyl, alkenyl, or alkoxy group of from 1to 8 carbon atoms, or R can be phenyl or methoxyphenyl.

Z can be thienyl, fury], phenyl; or Z can be mono-, diortrimethoxyphenol; monoor dichlorophenyl, or dichlorophenoxy. R and R canbe hydrogen, methyl, or ethyl, and can be the same or different.

DETAILED DISCUSSION The oxazolines suitable for the practice of thisinvention can be readily prepared from alkanolamines corresponding tothe formula:

R c cu ou where R and R have the same meaning as set forth hereinbefore,and a suitable acid. When Y is CH=CH, the acid is acetic acid; and whenY is the acid is an alkyl or alkenyl acid corresponding to the formula RCH- OOH. When Y is (CI-I a suitable acid is phenyl alkanoic orsubstituted phenyl alkanoic acid. These oxazolines are prepared by knownmethods, e.g., the method of Purcell, U.S. Pat. No.

3,336,145, which is incorporated herein by reference.

When Y is CH=CI-I or I -CH=C-R2:

Z is provided by condensing the oxazoline with the appropriate aldehyde,e.g., benzaldehyde or substituted benzaldehyde by known methods, e.g.,by the method of H. L. Wehrmeister, J. Org. Chem. 27, 4418 (1962).

The compounds of the present invention have been found to exert adepressant action of the central nervous system when tested understandard and accepted pharmacological procedures, in animals, such asmice and rats. They are, therefore, deemed to possess utility inexperimental and comparative pharmacology and are of value to treatconditions in animals. such as valuable domestic animals, and inlaboratory animals, such as mice, rats and the like, responsive totreatment with central nervous system depressant agents. Specifically,the compounds may be employed to induce a calming effect in animals.

In the pharmacological evaluation of the biological activity of thecompounds of this invention, the in vivo effects were tested by threedifferent tests. In one, the oral toxicity was determined byadministration to a group of laboratory mice. A trained observer watchedthe mice closely for several hours and noted decreased motor activity.The second test was the so-called jiggle cage method, a techniquedescribed by R. A. Turner, Screening methods in Pharmacology, page 89,published 1965, Academic Press, New York, and summarized in Example 1.The third test was that described by Horn, Biometrics, 12:311 (1956). Inthis test, laboratory mice received the test compound (two mice per doselevel) at one-half log-dosage intervals by intravenous injection. Theanimals were observed by trained observers and pharmacological signs oftranquilization were noted. The median lethal dose (LD and the medianeffective dose (MED for tranquilization were estimated. The safetyfactor was taken as the ratio of LD /med The compounds of this inventionare active as central nervous system depressants at a dose of about 0.01to about 1,000 mg/kg.

The invention will be better understood withreference to the followingexamples. It is understood, however, that the examples are intended forillustration only and it is not intended that the invention be limitedthereby.

EXAMPLE 1 4,4-Dimethyl-2-(Z-p-methoxyphenylethenyl)-2- oxazoline(P-1727) was synthesized by the method of H L. Wehrmeister, J. Org.Chem. 27, 4418 (1962) from o-anisaldehyde and2,4,4-trimethyl-2-oxazoline. The product had a boiling point at 0.2-0.25torr of 146-l51; it analyzed 72.47% C, 7.86% H, 6.32% N, neutralequivalent 237.4. Calculated values are 72.69% C, 7.41% H, 6.06% N, andneutral equivalent 231.3.

Animals (rats) were tested for tranquilizer activity by the jiggle cagemethod of R. A. Turner, Screening Methods in Pharmacology, page 89,Academic Press, New York (1965). In this method, a cage is suspendedfrom a rope and rests lightly on a pneumatic bed connected by a tube toa transducer. Activity in the cage results in changes of pressure on thepneumatic bed. The transducer changes these pressure variations toelectrical impulses which are continuously recorded on a chart, makingit possible to quantitate the amount, severity and frequency of themovement. The rats were fasted for 48 hours prior to testing to insure ahigh level of activity in the test cage.

At the time of the test, each rat was weighed and placed in the jigglecage. All activity of the rat was measured by the pneumatic sensor. Therat was then removed from the cage and dosed with either a testmaterial, negative control material, or standard material.

The rat was then placed in its original cage for 30 minutes. Followingthis, the rat was returned to the jiggle cage for minutes and allactivity recorded. The test, control, and standard material were givento the rats via stomach tube.

The above compound (P-l727) was tested on three rats using the abovetime schedule. With each run a standard, chlordiazepoxide hydrochloride,and negative control test were performed on at least one rat. Both thestandard and the test compound were administered as a suspension inwater with 1% tragacanth. The negative control was l percent tragacanthin water.

The standard and all test substances were administered by stomach tubeat a dosage level of 1 mg per 100 grams of body weight. The resultsobtained are as follows:

ACTIVITY DATA Average *Activity After Material Dose Activity BeforeMaterial Dose Corrected Activity Positive Control minus CorrectedActivity Condition.

The higher the score, the more tranquilizing activity exhibited by thematerials.

The results show that P-1727 is about equal in activity to the standard.

EXAMPLE 2 2-( 2-p-chlorophenylethenyl )-4,4-dimethyl-2- oxazoline(P-l581 was synthesized from 2,4,4-trimethyl-2-oxazoline andp-chlorobenzaldehyde.

The acute LD by oral administration to mice was determined to be 2725 i340 mg/kg. The LD was 1,500 mg/kg and the LD was approximately 5,400mg/kg. Animals receiving the compound were observed to be tranquilized.

The compound was tested by the method of Horn, described above. It wasdissolved in polyethylene glycol 300 and was administered intravenouslyat dosage levels of 10, 32, and 320 mg/kg to mice, two animals perdosage level. The dilution was such that each animal received a dose of1 ml of solution per kilogram of body weight. A trained observer watchedthe animals for evidence of central nervous system depressant activityin general and tranquilizing activity in particular. The dosage at whichthese signs became apparent was reported as the median effective dose(MED and the safety factor, the ratio LD /MED was determined. The LD wasdetermined to be mg/kg (range 56-560 mg/kg). The median effective dosewas 18 mg/kg (range 5.6-56) and the safety factor was 10.0.

EXAMPLE 3 2-(2-m-Chlorophenylethenyl)-4,4-dimethyl-2- oxazoline (P-l895)was prepared by reacting mchlorobenzaldehyde with2,4,4-trimethyl-2-oxazoline.

The acute LD by oral administration to mice was determined to be 1080 i166 mg/kg. The LD was 900 mg/kg and the LD was 1 ,600 mg/kg. Animalsreceiving the compound were strongly tranquilized.

The compound was tested by the method of Horn as described in Example 2.The LD was 100 mg/kg (range 32-320) and the median effective dose fortranquilization was 18 (range 56-56). The safety factor was 5.6.

EXAMPLE4 3,S-Dimethoxybenzaldehyde was reacted with2,4,4-triethyl-2-oxazoline to produce 2-[2-(3,5-

dimethoxyphenyl l -methylethenyl]-4,4-dimethyl-2- oxazoline (P-l64l b.p.l7l-l73 at 0.25 mm. It was administered to mice to determine the acuteoral toxicity and a trained observer studied the anminals fortranquilizing activity. The oral LD was determined to be over 5 g/kg andthe animals receiving it were observed to be highly tranquilized. Thecompound is administered orally to animals in need of tranquilizing in adosage of from about 100 to about 1,000 mg/kg.

EXAMPLE 5 The experiment of Example 2 was repeated in all essentialdetails except that 2,4,4-trimethyl-Z-oxazoline was substituted for2-ethyl-4,4-dimethyl-2-oxazoline. The product obtained was 2-(2-ochlorophenylethenyl)-4,4-dimethyl-2-oxazoline (P-1888), b.p. 141(0.48 mm) 148 (0.65 mm). The LD by oral administration was determined tobe 2,800 i 305 mg/kg. The LD was 1,500 mg/kg and the LD was 4,000 mg/kg.Animals receiving'it were tranquilized. At thetoxic dose levels thecompound caused convulsions. The compound is administered orally toanimals in need of tranquilizing in a dosage of from about 56 to about560 mg/kg.

EXAMPLE 6 4,4-Dimethyl-2-[2-(Z-thienyl)ethenyl]-2-oxazoline (P-l894) wassynthesized by reacting 2-thiophenecarboxaldehyde with2,4,4-trimethyl-2-oxazoline.

The acute LD in mice by oral administration was 1,900 i 100 mg/kg. TheLD was 1,650 and the LD was 2,800 mg/kg. Animals receiving the compoundwere tranquilized.

The compound was tested by the method of Horn described in Example 2.The LD,-,,, by intravenous administration was 180 mg/kg (56-560) and themedian effective dose for tranquilization was 18 mg/kg (5.6-56) and thesafety factor was 10.

EXAMPLE 7 3,4,5-Trimethoxybenzaldehyde was reacted with2,4-4-trimethyl-Z-oxazoline as described in Example 1 to produce4,4-dimethyl-2-[ 2-( 3 ,4,5- trimethoxyphenyl)ethenyl]-2-oxazoline(P-1730), mp. 116-118.

The aetue oral toxicity was determined by administration to mice. TheLD,-,,, was 1,400 i 233. The LD was 350 and the LD was 2,600. Animalsreceiving the product were observed to be tranquilized.

The compound was tested by the method of Horn. The LDsa by intravenousadministration was 180 (56-560) mg/kg. The median effective dose fortranquilization was 10 (3.2-320) and the safety factor was 18.0.

EXAMPLE 8 4,4-Dimethyl-2-( Z-p-methoxyphenyll-methylethenyl)-2-oxazoline (P-1642) was synthesized from oanisaldehydeand 2-ethy1-4,4-dimethyl-Z-oxazoline. The product distilled at l51164Cat a pressure of 02-025 torr. It analyzed 73.01% C, 7.96% H, 6.12% N,neutral equivalent 243.3. Calculated values were 73.44% C, 7.81% H,5.71% N, neutral equivalent 245.3.

The acute oral toxicity was determined by administration to mice. The LDwas 2,500 i 550 mg/kg. The LD was 800 and the LD was 6,700 mg/kg.Animals receiving the compound were tranquilized.

The compound was additionally tested by the method of Example 1 exceptthat P-1642 was substituted for P-1727. The results, which are asfollows, show that P-1642 is about as active a tranquilizer as thestandard.

ACTIVITY DATA ACTIVITY DATA-Continued Average 2 of Evaluation RatActivity Value No. Condition Scores (ZS) 25-600 4 Control (neg) 624 1.04Test 3 41 .07

5 Control (neg) 1289 2.15 Control (post) 425 .71

*This data rejected and not used in further calculations of activity onthe basis of the relative inactivity of the rat under conditions ofcontrol.

ACTIVITY RESULTS No. of Corrected* Activity* Animals Condition ActivityCoefficient 1 Standard 0.029 0.301 2 Test 0.036 0.294 1 Positive 0.330

Control *Aetivity After Material Dose Activity Before Material Dose**Corrected Activity Positive Control minus Corrected ActivityCondition.

The higher the score, the more tranquilizing activity exhibited by thematerial.

EXAMPLE 9 tures.

The high-melting isomer was tested by the method of Horn. The LD byintravenous administration was 1 mg/kg (56560.0). The median effectivedose for tranquilization was 18 mg/kg (5.6-56.0) and the safety factorwas 10. Animals receiving the compound were tranquilized.

EXAMPLE l0 4,4-Dimethyl-2-(2-phenylethenyl)-2-oxazoline (P-l 886) wasprepared by reacting benzaldehyde with 2,4,4-trimethyl-2-oxazoline. Theproduct had a boiling point of 1 12 at 0.45 mm. The nmr spectrum wasconsistent with the proposed structure.

The compound was tested by the method of Horn. The LD by intravenousadministration was 180 mg/kg (56.0-5600 mg/kg). The median effectivedose for tranquilization was 5.6 mg/kg 1.8-1 8.0) and the safety factorwas 32.0.

EXAMPLE 1 l 3-Methoxybenza1dehyde was reacted with 4,4-dimethyl-2-ethyl-2-oxazoline by the method of Example 1 to produce2-[2-(3-methoxyphenyl)-lmethylethenyl]-4,4-dimethyl-2-oxazoline (P- l643 b.p. 138 at 0.1 mm toat 0.25 mm. The LD by oral administration to'rnice was over 5.0 g/kg. The LD was not determined. Animals receiving thecompound were tranquilized. The compound is administered orally toanimals in need of tranquilizing in a dose of from about 100 to about1,000 mg/kg.

EXAMPLE l2 4,4-Dimethyl-2(2-a-furylethenyl)-2-oxazoline (P-l906) wasprepared by reacting furfural with 2,4,4-trimethyl-2-oxazoline. Theproduct had a boiling point of 87 at 0.14 mm and the nmr spectrum andinfra-red absorption spectrum were consistent with the proposedstructure. The oral LD by administration to mice was 50 mg/kg; theLD,-,., was 212 and the LD was 300 mg/kg.

The compound was tested by the method of Horn. The LD by intravenousadministration was 32 mg/kg (100-100.0). The median effective dose fortranquilization was 3.2 mg/kg and the safety factor was 10.0.

EXAMPLE 13 Benzaldehyde was reacted with 4,4-dimethyl-2-mcthoxymethyl-Z-oxazoline (derived from methoxyacetic acid) to produce2-(2-phenyl-l-methoxyethenyh- 4.4-dimethyl-Z-oxazoline (P-l907), b.p.122 (0.3 mm) The LD,-, by oral administration to mice was 2.8 g/kg. TheLD was 1,500 mg/kg and the LD was 4,500 mg/kg. Animals receiving it werestrongly tranquilized.

The compound was tested by the method of Horn. The LD by intravenousadministration was 100 mg/kg (323 20.0) and the median effective dosefor tranquilization was 18.0 mg/kg (5.6-56.0). The safety factor was5.6.

EXAMPLE l4 3,5-Dimethoxybenzaldehyde was reacted with 4,4-dimethyl-2-(9-decenyl)-2-oxazoline (Pl729) by the method of Example 1 toproduce 2-[2-(3,5-dimethoxyphenyl)-l-(8-nonenyl)-ethenyl]-4,4-dimethyl-2-oxazoline(P-l729), b.p. 214 0.4 mm) 217 013 mm); 2022 12 (0.2 mm). it wasadministered to mice to determine the oral toxicity. The LD was greaterthan g/kg. Animals receiving the product were observed to be mildlytranquilized. The compound is administered orally to animals in need oftranquilizing in a dosage of from about 100 to about 1,000 mg/kg.

EXAMPLE l5 4.4-Dimethyl-2-(p-methoxybenzyl)-2-oxazoline (Pl 866) wasprepared by reacting p-methoxyphenylacetic acid with2-amino-2-methyl-l-propanol according to the methods known in the art,e.g., R. F. Purcell, U.S. Pat. No. 3,336,145.

The acute oral toxicity was determined by administration to mice. The LDwas 1,900 i 465 mg/kg. The LD was 400 and the LD was 4,000 mg/kg.Animals receiving the product were tranquilized.

The compound was additionally tested by the method of Example 1 exceptthat P-l866 was substituted for P-l727.

The results obtained, which show that P-1866 is about twice as active atranquilizer as the standard, are as follows:

*Activity After Material Dose Activity Before Material Dose *CorrectedActivity Positive Control Corrected Activity C ondition The higher thescore. the more tranquilizing activity exhibited.

EXAMPLE 15A The foregoing experiment was repeated in all essentialdetails except that a compound structurally similar to Pl 866 was used.The compound was 4,4-dimethyl- 2-(4-methoxyphenyl)-2-oxazoline. It hadno tranquilizing activity.

The compound was also tested by the method of Horn. The LD byintravenous administration was 180 (56560.0). The median effective dosefor tranquilization was 56 (180-180.0). The safety factor was 3.2.

EXAMPLE l6 (R,S)-4-Ethyl-2-(p-methoxybenzyl)-2-oxazoline (Pl89l) wasprepared by reacting Z-amino-l -butanol with p-methoxyphenylacetic acid.

The acute LD by oral administration to mice was not determined, but theacute LD was 5,000 mg/kg.

Animals receiving the compound were tranquilized.

The compound was additionally tested by the method of Horn. The LD byintravenous administration was 180 (560-5600) mg/kg and the medianeffective dose for tranquilization was 5.6 mg/kg (l.8l8.0). The safetyfactor was 32.0.

EXAMPLE l7 5 ,6-Dihydro-2-(p-methoxyphenylmethyl l ,3- oxazine (P-1899),b.p. 117 at 0.22 mm, was prepared as follows:

4-Methoxyphenyl acetic acid, 49.8 g (0.3 mole), and 3-aminol-propanol,45.1 g (0.6 mole), were dissolved in ml xylene. The mixture was heatedwith stirring at l 75C at reflux, removing some xylene toward end. Theproduct was probably the amide at this point. The remaining xylene wasremoved by distillation and the residue was distilled at 0.4 mm, at140-160C. The

washed .with 10% NaHCO solution, then redistilledat 104 (0.15 mm) 121(0.24 mm). The distillate was dissolved in 100 ml of benzene andextracted twice with 50 ml portions of 3N l-lCl. The extract was madealkaline with Na CO and extracted with a mixture of benzene andchloroform. The extract was dried, filtered and the solvent was strippedby distillation. The product was then distilled at 117 (0.2 mm).

The acute oral LD,-, by administration to mice was 3,400 mg/kg. The LDwas 2,400 mg/kg and the LD was 4,800 mg/kg. Animals receiving thecompound were tranquilized.

The compound was additionally tested by the method of Horn; The LD byintravenous administration was 56.0 (18.0-180.0) mg/kg, and the medianeffective dose for tranquilization was 5.6 mg/kg (1.8l8.0). The safetyratio was 10.0.

, EXAMPLE l8 2-Benzyl-4.4-dimethyl-2-oxazoline (P-1890), b.p. 83-86 at1.0 mm, was made from phenylacetic acid and 2-amino-2-methyl-l-propanolby the method of Example 15. The acute oral LD by administration to micewas 1,400 mg/kg. The LD was 600 mg/kg and the LD was 2,400 mg/kg. Theanimals receiving it were tranquilized.

The product was additionally tested by the method of Horn. The LD byintravenous administration was 180.0 (56.0560.0) mg/kg and the medianeffective dose for tranquilization was 3.2 mg/kg (1.010.0). The safetyfactor was 56.0.

EXAMPLE 19 2-(2-Dichlorophenoxymethyl)-4,4-dimethyl-2- oxazoline(P-1902) was prepared by reacting 2,4-dichlorophenoxyacetic acid with2-amino-2- methyl-l-propanol.

The acute LD by oral administration to mice was determined to be 925 i170 mg/kg. The LD was 500 and the LD was approximately 1,800 mg/kg.Animals receiving the compound were tranquilized.

The compound was further tested by the method of Horn. The LD byintravenous administration was 180.0 (56.0560.0) mg/kg. The medianeffective dose for tranquilization was 32.0 mg/kg (100-1000) and thesafety factor was 5.6.

EXAMPLE 20 4,4-Dimethyl-2-(2-p-methoxyphenylethyl)-2- oxazoline (P-1882)was prepared from p-methoxyphenylpropionic acid and2-amino-2-methyl-lpropanol.

The oral LD by administration to mice was 2,800 110 mg/kg. The LD was2,400 mg/kg and the LD was 5,600 mg/kg. Animals receiving the compoundwere tranquilized. The compound was tested by the method of Horn. The LDby intravenous administration was 180.0 (56.0- 60.0) mg/kg, and themedian effective dose for tranquilization was 18 mg/kg (5.6-56.0). Thesafety factor was 10.0.

EXAMPLE 21 2-[ 1,2-Bis(4-methoxyphenyl)ethenyl]-4,4-dimethyl-2-oxazoline (P-1728) was prepared by reacting 4- methoxyphenyl aceticacid with 2-amino-2-methyl-lpropanol and condensing the product therebyobtained with p-methoxybenzaldehyde. The boiling point was about223 at038mm. The nmr spectrum was consistent with the proposed structure.

The oral LD by administration to mice was higher than 5.0 g/kg. The LDwas near 5.0 g/kg. Animals receiving the compound were mildlytranquilized.

The compound was tested by the method of Horn. The LD by intravenousadministration was greater than 320.0 mg/kg. The median effective dosefor tranquilization was 5.6 mg/kg (l.818.0) and the safety factor wasgreater than 56.

EXAMPLE 22 The experiment of Example 9 was repeated in all essentialdetails except that 3,S-dimethoxybenzaldehyde was substituted forp-chlorobenzaldehyde. There was obtained2-[2-(3,5-dimethoxyphenyl)-lphenylethenyl]-4,4-dimethyl-2-oxazoline(P-1644), b.p. 206-208 at 0.25 mm. The nuclear magnetic resonancespectrum and the infra-red absorption spectrum were consistent with theproposed structure.

The compound was tested by oral administration to mice. The LD was 1525i 350 mg/kg. The LD was 800 and the LD was 3,275 mg/kg. Animalsreceiving the compound were tranquilized.

The compounds of this invention are weakly alkaline and readily formsalts with most acids. Many of these salts are water-soluble andadvantageously can be used for administering these compounds. Theinvention therefore contemplates the administration of pharmaceuticallyacceptable salts of the disclosed compounds as well as the unneutralizedcompounds themselves.

I claim:

1. A method of tranquilizing an animal comprising the oral orintravenous administration to said animal of a tranquilizing amount of acompound, or a pharmaceutically acceptable salt thereof, correspondingto the formula where n is l or 2; Y is (CH;),,, where n is l or 2, or Yis where R is hydrogen, or an alkyl or alkenyl group of l to 8 carbonatoms, or alkoxy; Z is thienyl; furyl; phenyl or mono-, di-, ortrimethoxyphenyl; or monoor dichlorophenyl; or dichlorophenoxy; R and Rare hydrogen, methyl or ethyl and can be the same or different.

2. The method of claim 1 wherein Z is thienyl.

3. The method of claim 1 wherein Z is 4,6- dichlorophenyl.

4. The method of claim 1 wherein Z is dimethoxyphenyl.

5. The method of claim 1 wherein Z is trimethoxyphenyl.

6. The method of claim 1 wherein Z is methoxyphenyl.

7. The method of claim 1 wherein Z is furyl.

8. The method of claim 1 wherein Z is phenyl. where n is l or 2. 9. Themethod of claim 1 wherein Z is mono- 14. The method of claim 1 where Yis chlorophenyl.

10. The method of claim 1 wherein Z is 2,4- 1 dichlorophenoxy. 5-CH==C-R 11. The method of claim 1 wherein R and R are methyl. Where Ris hydrogen or an alkyl or alkenyl group of 1 12. The method of claim 1wherein R is ethyl. to 8 carbon atoms or alkoxy. 13. The method of claim1 wherein Y is -(CH 'UNTE'EED sTATEs PATENT OFFICE TEFICATE 0F CGRRECTWNPatent No. 3, 876 7'70 Dated APril 8 1975 Inventor(s) Herbert L.Wehrmeister It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 26, "of" should read on Column 2, line 56, "LD /medshould read LD /MED 0 Column 4, line 52, "anminals" should read-animals- Column 5, line 63, "ZS-600" should read -ZS;'-600-- Column 6,line 5, "zs-soo" should read ZS-;-600- Signed and Scaled this fourth Dayof May 1976 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Altvsting Officer (mnmissiom-r oj'lalunrsand Trademarks

1. A METHOD OF TRANQUILIZING AN ANIMAL COMPRISING THE ORAL ORINTRAVENOUS ADMINISTRATION TO SAID ANIMAL OF A TRANQUILIZNG AMOUNT OF ACOMPOUND, OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, CORRESPONDINGTO THE FORMULA
 2. A gelatinous mixture for application to human skin,comprising: 25 to 90% by weight of isopropanol, 0.1 to 5% by weight of apreservative selected from the group consisting of sorbic acid, butylpara-hydroxybenzoate and methyl para-hydroxybenzoate, 0 to 5% by weightof polyvinyl pyrrolidone, 5 to 50% by weight of a film forming agentselected from the group consisting of monoisopropyl ester of polyvinylmethylether and polyvinyl methylether, 1.96 to 3% by weight ofwater-soluble polyacrylic acid crosslinked with 1% of polyallyl sucrosehaving an average of about 5.8 allyl groups for each sucrose molecule. 2to 3% by weight of polyoxyethylene cocoamine having 15 oxy groups. 2.The method of claim 1 wherein Z is thienyl.
 3. The method of claim 1wherein Z is 4,6-dichlorophenyl.
 3. A gelatinous mixture for applicationto human skin, comprising: 63 to 80% by weight of isopropanol, 0.1 to 5%by weight of a preservative selected from the group consisting of butylpara-hydroxybenzoate and methyl para-hydroxybenzoate 1.0 to 5% by weightof polyvinyl pyrrolidone, 31 to 50% by weight of polyvinyl methylether,2 to 3% by weight of water-soluble polyacrylic acid crosslinked with 1%of polyallyl sucrose having an average of about 5.8 allyl groups foreach sucrose molecule, and 2.0 to 3% by weight of polyoxyethylene having15 oxy groups cocoamine.
 4. A gelatinous mixture for application tohuman skin, comprising: 25 to 90% by weight of isopropanol, 0.1 to 0.4%by weight of sorbic acid, 0 to 2% by weight of polyvinyl pyrrolidone, 5to 20% by weight of water, 5 to 45% by weight of monoisopropyl ester ofpolyvinyl methylether, and 2 to 10% by weight of hydroxypropylcellulose.
 4. The method of claim 1 wherein Z is dimethoxyphenyl.
 5. Themethod of claim 1 wherein Z is trimethoxyphenyl.
 5. A gelatinous mixturefor application to human skin, comprising: 63% by weight of isopropanol,less than 5% by weight of methyl para-hydroxybenzoate and butylpara-hydroxybenzoate 1.0% by weight of polyvinyl pyrrolidone, 31% byweight of polyvinyl methylether, 2% by weight of water-solublepolyacrylic acid crosslinked with 1% of polyallyl sucrose having anaverage of about 5.8 allyl groups for each sucrose molecule, and 2% byweight of polyoxyethylene cocoamine having 15 oxy groups.
 6. Agelatinous mixture for application to human skin, comprising: 80% byweight of isopropylalcohol, less than 0.4% by weight of sorbic acid, 1%by weight of polyvinyl pyrrolidone, 5% by weight of distilled water, 5%by weight of hydroxypropyl cellulose, and 9% by weight of monoisopropylester of polyvinyl methylether.
 6. The method of claim 1 wherein Z ismethoxyphenyl.
 7. The method of claim 1 wherein Z is furyl.
 8. Themethod of claim 1 wherein Z is phenyl.
 9. The method of claim 1 whereinZ is monochlorophenyl.
 10. The method of claim 1 wherein Z is2,4-dichlorophenoxy.
 11. The method of claim 1 wherein R and R.sup.1 aremethyl.
 12. The method of claim 1 wherein R is ethyl.
 13. The method ofclaim 1 wherein Y is --(CH.sub.2).sub.n --where n is 1 or
 2. 14. Themethod of claim 1 where Y is